Cardiovascular disease is caused by a number of synergistic factors, the most important being a too high blood cholesterol level. Cholesterol is an essential building block for animal and human cells, since it is a component of cell membranes. Human cells can synthesize their own cholesterol, but cholesterol is also assimilated from food. Both processes play an important part in cholesterol metabolism.
Apart from its essential biological role as a building block for cellular membranes, cholesterol also has negative effects on human health, as a cause of cardiovascular disease (such as, for instance, myocardial infarction, stroke, and peripheral vascular disease), more specifically in relation to the occurrence of atherosclerotic lesions in the blood vessel wall. An elevated plasma cholesterol level is the most important predictive risk factor for the occurrence of cardiovascular disease and atherosclerosis.
In blood plasma, cholesterol is transported in so-called lipoproteins, which can be subdivided into a number of different classes, based on their diameter and specific density. The very-low-density lipoproteins (VLDL), the intermediate-density lipoproteins (IDL), the low-density lipoproteins (LDL), and the high-density lipoproteins (HDL) constitute the most important classes of lipoproteins.
Experimental and clinical studies have shown that the amount of cholesterol transported in the VLDL, IDL and LDL classes of lipoproteins (the so-called pro-atherogenic cholesterol) is a risk factor for the occurrence of cardiovascular disease. Cholesterol transported in HDL particles, in contrast, protects against the development of cardiovascular disease (anti-atherogenic cholesterol).
Randomized, placebo-controlled, prospective clinical studies have demonstrated that lowering plasma cholesterol has a favourable effect on the incidence of cardiovascular disease and on mortality. A prerequisite is, though, that the reduction in cholesterol should be due to a reduction in the pro-atherogenic cholesterol present in VLDL, IDL and LDL.
For the treatment and prevention of cardiovascular disease it is therefore imperative to reduce the pro-atherogenic cholesterol, and to increase, in absolute or relative proportion, the anti-atherogenic cholesterol.
A number of approaches are available to reduce plasma cholesterol. The most important are:
                to inhibit cholesterol biosynthesis;        to increase the removal of cholesterol (and/or its metabolites, specifically bile acids) from tissues into the intestinal lumen;        to reduce the absorption of cholesterol and bile acids from the gastrointestinal tract.        
Drugs that are nowadays used to inhibit cholesterol synthesis are often inhibitors of the enzyme hydroxymethyl-glutaryl-coenzyme A reductase (HMGCoA reductase), the rate-limiting enzyme in the synthetic pathway to cholesterol. These so-called “statins” are molecules that competitively inhibit enzyme action. Examples are simvastatin (“Zocor®”), pravastatin (“Pravachol®”) and atorvastatin (“Lipitor®”). Statins are generally chemically-synthesized derivatives of naturally-occurring fungal metabolites.
To increase cholesterol removal a bile acid-adsorbing resin can be used (for example cholestyramine, “Questran®”). Because of the adsorption of bile acids to the resin, their secretion in the stool is increased, and their re-absorption from the gut into the blood is reduced, resulting in a relative loss of bile acids from the body. Consequently, the liver increases the conversion of cholesterol into bile acids, resulting in a net increase in the secretion of cholesterol (metabolites) from the body. Because bile acids (by solubilizing cholesterol) are essential for the uptake of cholesterol from the lumen into the intestinal tissue, a reduction in bile acid content in the intestinal lumen will also result in a decreased cholesterol uptake.
Drugs that inhibit the active transport of cholesterol from the intestinal lumen to the blood by inhibiting cellular transport systems for cholesterol (and related sterols) in the intestinal epithelial cells are still under development. One such compound (“Ezetimibe®”) has recently been registered in some countries; other related drugs are still being tested in clinical trials.
In addition to the use of drugs, the above-mentioned goals can also be reached by the use of naturally-occurring compounds, or of compounds derived from natural products (Hassel, 1998). A statin-like compound occurs spontaneously in so-called “red rice”, a strain of rice carrying a mould producing lovastatin. This fungal metabolite is identical to the cholesterol-reducing medicament “Mevacor®”. Another example is the occurrence, in plants, of so-called phytosterols, which competitively inhibit the intestinal uptake of cholesterol and bile acids. Phytosterols are nowadays used as cholesterol-lowering additives in the margarines “Benecol®” and “Becel Proactif®”.
However, there still exists a need for cholesterol-lowering preparations, specifically for use in the food industry, and preferably aimed at human nutrition.